Implantable device for intraperitoneal drug delivery

ABSTRACT

Drug delivery devices, medicaments, and methods are provided for the intraperitoneal treatment of ovarian cancer. An implantable device for drug delivery includes an elongated, flexible device having a housing defining a reservoir that contains a drug in solid or semi-solid form, and configured to be wholly deployed within the peritoneal cavity of a patient and continuously release a therapeutically effective amount of the drug over a period of at least 24 hours. A medicament includes cisplatin for administration into the peritoneal cavity of a patient continuously over a treatment period of at least 24 hours. A method of drug delivery includes implanting within the peritoneal cavity of a patient an elongated, flexible device having a reservoir containing a drug, solubilizing the drug at least in part with peritoneal fluid, and releasing an effective amount of the solubilized drug from the reservoir continuously for a period of at least 24 hours.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/400,216, filed Nov. 10, 2014, which is a national stage ofPCT/US2013/040405, filed May 9, 2013, which claims priority to U.S.Provisional Application No. 61/644,497, filed May 9, 2012. Theseapplications are incorporated herein by reference.

TECHNICAL FIELD

The present disclosure generally pertains to implantable drug deliverysystems and methods. Certain embodiments specifically pertain to systemsand methods for local drug delivery and controlled release of drugs inthe treatment of ovarian cancer.

BACKGROUND

Ovarian cancer is one of the most common types of cancer, with aprevalence of 13.1 per 100,000 women in the United States and a deathrate of 8.8 per 100,000 women. (Homer, et al. (eds.) SEER CancerStatistics Review (1975-2006)). Ovarian cancer is relativelyasymptomatic at its early stages with rare cases of incidental earlydiagnosis due to other diseases or symptoms. In about three-quarters ofall cases of ovarian cancer, the patients present with peritonealmetastasis at the time of diagnosis. (Colombo, et al., Gynecol. Oncol.122, 632-640 (2011)).

The standard primary treatment for advanced ovarian cancer includescytoreduction surgery where the bulk of the tumor is removed viaminimally invasive laparoscopic surgery, followed by intravenous (IV) orintraperitoneal (IP) chemotherapy with a platinum-based agent such ascisplatin.

The IP regimen requires surgeons to implant a catheter connected to aport (such as the BardPort®) during the cytoreduction surgery.Specifically, following the debulking of large visible tumors, two 5 mmincisions are made at the upper right and lower right quadrants of theabdomen. The port is inserted through the incision at the upper rightquadrant and sutured subcutaneously. The tip of the catheter is tunneledsubcutaneously to the incision in the lower right quadrant of theabdomen where it will enter the peritoneal cavity. Once every threeweeks, the patient receives an infusion of 2 liters of cisplatinsolution through the port and into the peritoneal cavity.

Although clinical trials have shown that the IP chemotherapy prolongssurvival, many patients drop out of treatment due to catheter-relatedcomplications. (Armstrong, et al., N. Engl. J. Med. 354, 34-43 (2006)).For example, the implantation sites are prone to infection andinflammation over the period of treatment and the long catheter issusceptible to obstruction.

Pharmacokinetic studies have shown that the peak concentration ofcisplatin in the peritoneal cavity reaches a level 20 times that in thesystemic compartment, and the total area-under-curve concentration ofcisplatin is 12 times that of systemic circulation if cisplatin isadministered directly into the peritoneal cavity. (Markman, The LancetOncology 4, 277-83 (2003); Casper, et al., Cancer Treatment Reports 67,235-38 (1983)). The Gynecology Oncology Group has conducted large phaseIII trials, comparing three different IV cisplatin treatment regimens toIP cisplatin treatment and found the latter to be able to prolongoverall survival from 49.7 months in IV treatment to 65.6 months(p=0.03). (Armstrong, et al., N. Engl. J. Med. 354, 34-43 (2006)).However, 83% of subjects completed all cycles of IV therapy, but only42% of subjects completed all cycles of IP therapy. The primary reasonfor dropping-out of IP treatment is catheter-related complications.

Furthermore, many medical practitioners hesitate to recommend the IPtreatment modality due to the lack of familiarity among clinicians withperitoneal administration and catheter-placement techniques. Thiscomplex procedure currently can only be performed at premier cancercenters by trained personnel. Accordingly, there is a need for analternative to IP administration that eliminates catheter-relatedcomplications to allow more patients to enjoy the benefits of IPtherapy.

Alternative approaches to IP administration have been proposed, such asformulating cisplatin with a polymeric matrix material, for example inparticle form, to provide a depot for extended release of the drug.Reported depot approaches involve drug laden polymeric particles thatare administered to the desired site and release the drug over a periodof time. One disadvantage of polymeric particles is that they require asignificant amount of polymeric material in the formulation to reliablycontrol the release of the cytotoxic agent. The mass of polymersignificantly exceeds the mass of drug in such formulations. Forexample, repeated administration could result in the accrual ofpolymeric materials within the patient and could limit the frequency ofadministration possible. Another disadvantage of this approach is thatthe drug administration is essentially irreversible. Thus, if the dosageis administered for the entire therapy, one cannot readily, if at all,remove the drug if the therapy is not tolerated. A third disadvantage ofpolymeric particle administration is that release from such formulationsis strongly affected by the chemistries of the drug and polymericmaterial. Consequently, the rate of release is limited once thematerials are selected, and varying release rates is very complicated.For example, bulk polymers, such as polylactic acid, result in non-zeroorder releases while a constant, zero-order release rate is oftenpreferred in drug delivery. Liposomes have also emerged as a populardrug-carrying vehicle in recent years;

however, for the same reasons as with the polymer materials, theseformulations are not ideal for the treatment of ovarian cancer.

Paclitaxel is another commonly used drug in the current ovarian cancertreatment. It is dosed IV 135 mg/kg post-surgery over 24 hours or IP 60mg/kg on Day 8. It is a hydrophobic small molecule that has a log P ofabout 3.5 (DrugBank, DB01229). Several patents disclose incorporatingpaclitaxel into degradable polymer microparticles for drug releaselocally. For example, U.S. Pat. No. 6,855,331 to Vook et al. disclosesreleasing hydrophobic drugs using the polylactic glycolic acid (PLGA)particles. However, the PLGA particles could only sustain a relativelylinear release profile up to about Day 11 before a sharp drop in therelease rate was observed. Those microparticles could only release forup to 25% of the paclitaxel loaded into the microparticles before theplateau.

In another example, U.S. Pat. No. 6,479,067 to Dang discloses a methodof using poly(phosphoester) particles to release paclitaxel and othersmall molecules such as lidocaine, cisplatin, and doxorubicin. Therelease of cisplatin from these microparticles, however, is not wellcontrolled, as 45% of the loaded cisplatin was released through Day 1 inone of the in vitro release experiments, and another 30% was released inthe subsequent 3 days. In another in vitro release experiment withcisplatin, only 5% of cisplatin was released over 3 days, and almost nocisplatin was released over the rest of the 14 days of in vitro release.The release of paclitaxel was the most consistent among all the drugsmentioned.

The only in vivo efficacy study performed was with OVCAR-3 ovarian tumorcell line which compared microparticles containing palictaxel at a doseof 10 and 40 mg/kg to free paclitaxel of 10 and 40 mg/kg. The resultsshowed that at the 10 mg/kg dose, there is no significant differencebetween the microparticle formulation and free paclitaxel (70 and 60days respectively); at 40 mg/kg, the median survival of microparticleformulation is about 110 days, while that of free paclitaxel is about 70days. This dose is quite high compared with conventional dosing in mice.The standard maximum dose of paclitaxel in the mouse model is 20 mg/kg.(Balthasar, et al., Cancer Chemother. Pharmacol. 68, 951-58 (2011)).However, 50 mg/kg has been used to investigate the neurophysiologicaland neuropathological damage in mice. The dose of 20 mg/kg is,therefore, a better comparison between the efficacy of themicroparticles and free paclitaxel.

In another proposed alternative therapy, a group from University ofCalifornia, San Diego recently developed a type of CD44-targetinghyaluronan-based microparticle that can encapsulate cisplatin. (DeStefano, et al., Cancer Chemother. Pharmacol. 68, 107-16 (2011)). CD44is a surface ligand that is expressed on some types of ovarian cancercells and hyaluronan is a natural ligand for CD44. However, theseparticles can only increase cisplatin uptake for CD44-positive ovariancancer cell lines. Although these particles managed to prolong cisplatinhalf-life in the peritoneal cavity (when administered IP) to 124 minutesfrom 18 minutes in IP bolus injection, it still decreased quickly.

Accordingly, a new ovarian cancer treatment regimen that avoids theprolonged use of a catheter, eliminates or minimizes the use depotmatrix materials in the drug formulation, is inexpensive, and is simpleto administer would be favorable for both clinicians and patients. Asignificant need therefore exists for new systems and methods for localdrug delivery and controlled release of drugs in the treatment ofovarian cancer. Improved systems and methods for continuous or extendedintraperitoneal delivery of drug are needed.

SUMMARY

In one aspect, a medicament for use in the treatment of ovarian canceris provided, including cisplatin for intraperitoneal administration intothe peritoneal cavity of a patient continuously over a treatment periodof at least 24 hours. In one embodiment, the cisplatin is releasedcontinuously from a drug delivery device implanted in the peritonealcavity of the patient.

In another aspect, a method of intraperitoneal delivery of drug to apatient is provided, including (i) implanting within the peritonealcavity of a patient an elongated, flexible device which includes ahousing defining a reservoir that contains a drug in solid or semi-solidform, (ii) solubilizing the drug at least in part with peritoneal fluid,and (iii) releasing an effective amount of the solubilized drug from thereservoir into the peritoneal cavity continuously for a period of atleast 24 hours. In one embodiment, the patient is in need of treatmentfor ovarian cancer and the drug includes cisplatin or anotherchemotherapeutic agent.

In yet another aspect, an implantable device for intraperitoneal drugdelivery is provided, including an elongated, flexible device whichincludes a housing defining a reservoir that contains a drug in solid orsemi-solid form, wherein the device is configured to be wholly deployedwithin the peritoneal cavity of a patient and continuously release atherapeutically effective amount of the drug over a period of at least24 hours.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a plan view of an implantable drug delivery device inaccordance with one embodiment of the present disclosure.

FIG. 1B is a cross-sectional view of the implantable drug deliverydevice of FIG. 1A, along line B-B.

FIG. 2 depicts a drug delivery device implanted in the peritoneal cavityof a human patient in accordance with one embodiment of the presentdisclosure.

FIG. 3 is an exploded view of a reservoir-based drug delivery device inaccordance with another embodiment of the present disclosure.

FIG. 4 is a graph showing the in vitro release profile for variousreservoir-based drug delivery devices.

FIG. 5 is a graph showing the cell viability of ovarian cancer cellsover time when exposed to various concentrations of cisplatin.

FIG. 6A is a graph showing in vivo cisplatin concentration over timeafter IP bolus injection.

FIG. 6B is a graph showing in vivo cisplatin concentration over timewith release from an implanted reservoir-based drug delivery device.

FIG. 7 is a graph showing in vivo tumor growth over time in miceinjected with various concentrations of SKOV3 luciferase-positive cells.

FIG. 8 is a graph showing the comparative tumor mass of mice havingreceived various IP cancer treatments.

FIG. 9 is a graph showing in vivo tumor growth over time in mice havingreceived various IP cancer treatments.

FIG. 10 is a graph showing the relative creatinine concentrations inmice having received various IP cancer treatments.

FIG. 11 is a graph showing the relative weight loss over time of micehaving received various IP cancer treatments.

DETAILED DESCRIPTION

Drug delivery devices, medicaments, and methods are provided to addresssome or all of the above-described needs. In particular, areservoir-based drug delivery device that can improve the currenttreatment regimen for patients with advance-staged ovarian cancer hasbeen developed. These devices and methods advantageously may decreasemorbidity due to catheter related complications, reduce systemic drugconcentration, and improve patients' well-being during the treatment.The devices and methods have been shown to control tumor growth withoutcausing significant side effects in a mouse model, strongly suggestingits usefulness and benefits, for example, in the treatment of ovariancancer in human patients.

In certain embodiments, the device is an implantable medical devicedesigned for local, continuous intraperitoneal release of one or moredrugs over an extended period. In particular, the devices, medicaments,and methods can be used in intraperitoneal (IP) chemotherapy, such aswith a platinum-based drug, such as cisplatin. In particular, the devicemay be a reservoir-based drug delivery device that can release cisplatinand/or other drugs in a highly reproducible and controlled manner.

Advantageously, the device is implanted once and therefore poses noproblem of a “carry over” effect in terms of foreign material betweenmultiple administrations associated with conventional catheter-based IPinfusions. In addition, the device advantageously is less dependent onthe relative chemistries of the drug and device components, as is thecase with conventional formulation-based approaches for extended drugdelivery. Moreover, the rate of release can be tuned by varying thearchitecture of the device, independently of the payload and method ofloading.

Advantageously, the reservoir-based device has a high packing ratio forthe drug and, therefore, alleviates the problem of having a large volumeof fluid infused into the peritoneal cavity. In addition, the chance ofan infection or inflammation is minimal because the need for a catheteris eliminated. Lastly, the device can release cisplatin or other drugsat a low and constant rate at the tumor site, thereby greatly reducingthe systemic concentration and achieving less drug side effects such asnephrotoxicity.

In certain embodiments, the drug delivery device is designed to be fullydeployed in the peritoneal cavity of a patient in need of treatment. Forexample, the surgeon may leave the device in the peritoneal cavitythrough the laparoscopic ports during cytoreduction surgery, instead ofthe tunneling procedure, before closing the wound. Such an approachshould eliminate catheter-related complications and improve surgeonacceptance. Removal of the device may be accomplished by minimallyinvasive surgery using laparoscopy. In other embodiments, the device isconstructed of a resorbable material so that no procedure is required toremove the device from the patient after release of the drug.

The Examples described below include preclinical results for localdelivery of cisplatin in an animal model of ovarian cancer. Notably, thedevice described in the study below will release continuously for up to18 weeks, allowing cisplatin to constantly act on the tumor cells overthe entire treatment period. The in vitro release experiment proved thatdevice is able to release linearly and reproducibly, and by engineeringthe number of release orifices, device dimensions, and/or other featuresof the device, the drug release rate may be controlled precisely.

I. Implantable Drug Delivery Devices

Certain embodiments of implantable drug delivery devices provided hereingenerally include a reservoir defined by/within a housing configured forintraperitoneal administration. The housing also may be referred toherein as the “device body” or the “wall.” The housing houses (e.g.,contains) a drug formulation and then releases the drug from thereservoir following implantation in a patient.

Non-limiting embodiments of the device are shown in FIGS. 1A-B and 2. Asshown in FIGS. 1A and B, the housing 12 of the device 10 may be aflexible, annular cylinder, with closed ends, with the reservoir 14being the defined by the inner surface of the annular cylinder wall.Drug formulation 18 fills the reservoir 14 defined by the inner wall ofhousing 12. The device may be elongated and flexible. In embodiments,the housing is sized and shaped for implantation wholly within theperitoneal cavity. FIG. 2 depicts the device 20 implanted in theperitoneal cavity of a human patient.

In one embodiment, as shown in FIG. 1A, the device 10 has atubular-shaped housing 12 with one or more apertures 16 extendingthrough the housing wall in spaced positions along the length of thedevice 10. In addition, or in an alternative embodiment, one or moreorifices may be provided in one or both ends of the housing.

The housing may be formed from material that is elastomeric, which mayreduce trauma to surrounding tissues upon implantation. In oneembodiment, the housing is sufficiently elastic, even while thereservoir is loaded with drug, to have a curled conformation, which maybe elastically straightened during implantation through a laparoscopicport, and elastically return to the original curled conformationfollowing release into the peritoneal cavity. For example, the housingmay be formed of silicone.

Release of the drug may be controlled by the housing. For example, drugmay be released throughout the entire length of the housing wall or aselected portion thereof. The housing may have one or more holes orapertures to provide a passageway for a physiological fluid in the IPcavity, at the site of deployment of the device in the patient, to flowinto the reservoir to solubilize a solid drug formulation disposedtherein. In addition or alternatively, the housing wall, or portionsthereof may be water permeable or porous to permit the physiologicalfluid to flow into the reservoir to solubilize the solid drugformulation. The solubilized drug may be released through all or aportion of the housing. For example, the solubilized drug may diffusethrough the housing wall itself or through one or more aperturesprovided in selected areas of the housing wall. Selected areas of thehousing wall, e.g., dimpled areas, may be made relatively thinner thanother parts of the housing wall to promote diffusion therethrough.

As used herein, the term “solubilized” includes pure solutions as wellas suspensions of drug particles dispersed in a liquid carrier. Suchsuspensions may include microparticulate or nanoparticulate forms of thedrug.

The delivery rate of drug from the housing may be affected by the shape,size, number and placement of the apertures. Other factors also mayaffect the delivery rate, such as the dissolution profile of the drugformulation. In alternative embodiments, release of the drug from thedevice may involve other mechanisms, such as osmotic pressure or surfaceerosion. In still other embodiments, the device may operate by acombination of release mechanisms.

The exact configuration and shape of the device may be selecteddepending upon a variety of factors including the location, route, andmethod of implantation, the composition and dosage of the drugformulation, the therapeutic application of the device, or a combinationthereof. The device may be designed to deliver a therapeuticallyeffective dose of the drug into the peritoneal cavity for local orregional effect.

In certain embodiments, the device is substantially filled with a solidor semi-solid form of the drug. Such configurations may maximize thedrug payload on board the device, reducing the size of the device neededto deliver a therapeutically effective dose of the drug over an extendedperiod. For example, the drug formulation desirably is a substantialfraction of the total volume of the entire device at the time ofimplantation. For example, the drug formulation portion may be more than50%, more than 70%, more than 90%, e.g., between 75% and 95% inclusive,of the total volume of the drug-loaded device. In certain embodiments,the solid or semi-solid drug formulation includes the drug in an amountof more than 50 percent by volume, more than 75 percent by volume, ormore than 90 percent by volume of the reservoir, and one or moreexcipients in a remaining amount of volume of the reservoir.

The drug delivery device may be sized and shaped for implantation whollywithin the peritoneal cavity. The outer surface of the device may besoft and smooth without sharp edges or tips, so as to avoid damagingtissues adjacent to the implanted device. In some embodiments theportion of the device implanted within the peritoneal cavity may havedimensions that do not exceed 3 mm in width or diameter. This generallywill facilitate the device being able to pass through an internal boreof a cannula or other laparoscopic access instrument inserted into theperitoneal cavity. In certain embodiments, the device housing has anouter diameter from about 1 mm to about 5 mm. The length of the devicecan vary, but generally will not be larger than necessary to possess thereservoir volume required to hold the desired drug payload. For example,the device housing may have a length from about 25 mm to about 500 mm,from about 25 mm to about 100 mm, or from about 50 mm to about 100 mm.In embodiments, the desired device dimensions may be calculated fromexperimental data.

For example, the cisplatin concentration to be maintained in theperitoneal cavity in human patients should be very close to that formice. The tumors in humans that remain after debulking surgery are lessthan 1 cm in diameter while the larger tumors growing in the peritonealcavity of the mice are also about 1 cm in diameter. The volume ofperitoneal fluid in human is, however, much larger than that of mice. Asimple method of estimating the volume difference is using the bodysurface area, which is linearly proportional to the volume of blood. Theaverage body surface area of a mouse is 0.0075 m² while that of a humanadult is about 1.85 m, or about 247-times larger. The clearancehalf-life from the peritoneal cavity in human is about 50 minutes, whilethat of mouse is about 25 min. Therefore, the targeted release rate tobe achieved in human should be approximately 100 times that of in mice.As discussed below, a treatment efficacy study showed that the averagecisplatin release rate is 23.6±5.0 μg/day in mice. Accordingly, anapproximate human device release rate may be around 2.4 mg/day.

In embodiments, the device is configured to administer cisplatin in vivoat an average rate from about 0.5 mg/day to about 31 mg/day. In apreferred embodiment, the device is configured to administer cisplatinin vivo at an average rate from about 1.5 mg/day to about 3.5 mg/day.For example, the device may be configured to maintain a concentration ofthe cisplatin in the peritoneal fluid of the patient of at least about0.5 μg/mL for at least 7 days, while releasing at an average rate of nomore than 5 mg/day.

In one embodiment, the device is configured to release the cisplatin invivo at a rate from about 0.5 mg/hour to about 10 mg/hour. For example,the device may release the cisplatin in vivo at a rate from 0.6 mg/hourto about 2.5 mg/hour.

In one embodiment of a device capable of administering in vivo (e.g., inperitoneal fluid) the therapeutic amounts of cisplatin described above,the device is configured to release cisplatin in vitro at a rate fromabout 15 mg/day to about 50 mg/day in phosphate buffered saline at 37°C. In other embodiments, the rate may be outside of this range.

The current treatment regimen for cisplatin is 100 mg/m² per dose, onedose for every 3 weeks, for 6 doses. The total payload for a humandevice, assuming the same treatment period of 18 weeks, is thusestimated to be 781 mg. In certain embodiments, the device contains from500 mg to 1000 mg cisplatin. There is most likely also a correlationbetween the body surface area of the patient and payload of the device.In one case, for example, the device housing may comprise an 8 mm outerdiameter, 5 mm inner diameter tube. Therefore, assuming a density ofabout 1 g/cm³ for the cisplatin powder, and a packing factor of 50%, thedevice housing would be about 80 mm long. Alternatively, if one wishedto deploy and retrieve the device through the lumen of a laparoscope,the outer diameter would likely be smaller. For example, if the housinghad an outer diameter of 4 mm and an inner diameter of 2 mm, then thelength of the housing would be approximately 497 mm in order to hold thesame drug payload. One skilled in the art can readily envisionvariations of this device design and design criteria with differentdrugs, housings, animal models, and the like.

In some embodiments, it may be easier to deploy and retrieve two or moresuch shorter devices. The advantage of such an approach is that no onedevice may be so long that it is difficult to deploy and retrieve. Inaddition, proper distribution of drug release within the IP cavity maybe best achieved by distributing devices within the cavity. The two ormore shorter devices optionally may be tethered together, for example tofacilitate retrieval.

In some embodiments, the housing defines multiple reservoirs, which mayfacilitate releasing two or more separate drug formulations from asingle device, releasing drugs at two or more different release rates,releasing drugs at two or more different times following implantation,or combinations thereof. For example, a first dose of the drug may bepre-programmed to release at a first time and a second dose of the drugmay be pre-programmed to release at a second, later time. The term“pre-programming” herein generally refers to designing and building thedevice to provide the selected release functionality.

In certain embodiments, the housing may be made from one material or acombination of materials. The materials desirably are biocompatible andsuitable for implantation into a patient. The housing generally is madeof a biocompatible polymeric material. In some embodiments, the housingincludes a material that is permeable to fluid. The permeable materialenables selective intake of fluid into the reservoir to solubilize thedrug in the reservoir. Alternatively, one or more apertures in thehousing may be configured to enable the selective intake of fluid intothe reservoir to solubilize the drug in the reservoir. As used herein,the term “solubilized” includes solutions of drug, fine suspensions ofdrug, or a combination thereof. Any portion of the housing may bepermeable to a solubilizing fluid, such as the container, the end cap,or portions or combinations thereof. In various embodiments, the housingis selectively permeable to water but is substantially impermeable todrug, limiting or preventing the drug from exiting the device throughthe housing wall. Alternatively, the housing may be substantially waterimpermeable.

The device housing may be made of biocompatible, non-resorbablematerials (such as silicone) or resorbable (e.g., biodegradable)materials (such as poly(glycerol sebacate)). The biodegradable materialshave the advantage of requiring only a single surgery of implantation,without the need to retrieve the device after releasing its payload.Poly(glycerol sebacate) (PGS) is also elastomeric. As used herein, theterm “resorbable” means that the housing, or a part thereof, degrades invivo by dissolution, enzymatic hydrolysis, erosion, or a combinationthereof. The degradation may occur at a time that does not interferewith the intended kinetics of release of the drug from the housing. Forexample, substantial resorption of the housing may not occur until afterthe drug formulation is substantially or completely released. In anotherembodiment, the housing is resorbable and the release of the drugformulation is controlled at least in part by the degradationcharacteristics of the resorbable housing.

In embodiments in which the housing is resorbable, the housing mayinclude one or more biodegradable or bioerodible polymers. Examples ofsuitable resorbable materials include synthetic polymers selected frompoly(amides), poly(esters), poly(ester amides), poly(anhydrides),poly(orthoesters), polyphosphazenes, pseudo poly(amino acids),poly(glycerol-sebacate), copolymers thereof, and mixtures thereof. In apreferred embodiment, the resorbable synthetic polymers are selectedfrom poly(lactic acids), poly(glycolic acids), poly(lactic-co-glycolicacids), poly(caprolactones), and mixtures thereof. Other curablebioresorbable elastomers include poly(caprolactone) (PC) derivatives,amino alcohol-based poly(ester amides) (PEA) and poly (octane-diolcitrate) (POC). In one embodiment, the housing is formed from acombination of a resorbable polyester, such as poly(lactic acid), and aliquid crystalline polymer (LCP).

Alternatively, the housing may be at least partially non-resorbable.Examples of suitable non-resorbable materials include materials such asmedical grade silicone, natural latex, PTFE, ePTFE, PLGA, stainlesssteel, nitinol, elgiloy (non ferro magnetic metal alloy), polypropylene,polyethylene, polycarbonate, polyester, nylon, or combinations thereof.Other examples of suitable non-resorbable materials include syntheticpolymers selected from poly(ethers), poly(acrylates),poly(methacrylates), poly(vinyl pyrolidones), poly(vinyl acetates),poly(urethanes), celluloses, cellulose acetates, poly(siloxanes),poly(ethylene), poly(tetrafluoroethylene) and other fluorinatedpolymers, poly(siloxanes), copolymers thereof, and combinations thereof.Combinations of any of these materials, or these and other materials,may also be employed.

In one embodiment, the material forming the housing may comprise an“antimicrobial” material, such as a polymer material impregnated withsilver or another antimicrobial agent known in the art.

In a preferred embodiment, the housing includes at least oneradio-opaque portion or structure to facilitate detection or viewing ofthe device by a medical practitioner, when the device is deployed invivo and/or as part of the implantation or retrieval procedure. In oneembodiment, the housing is constructed of a material that includes aradio-opaque filler material, such as barium sulfate or anotherradio-opaque material known in the art. Fluoroscopy may be the preferredmethod of viewing the device during deployment/retrieval of the device,providing accurate real-time imaging of the position and orientation ofthe device to the practitioner performing the procedure. Other imagingtechniques known in the art also may be used.

In one embodiment, the housing further includes at least one sutureloop, to aid in securing the implanted device and avoid or minimizedevice migration. For example, suture loops may be provided at one orboth ends of the device.

The housing may include a drug reservoir aperture or valve (e.g., aseptum) or other orifice, so that a fluid can be injected into thereservoir. For example, it may be useful to inject a sterile saline intothe device immediately prior to implantation of the device to “kickstart” the drug dissolution process and reduce the lag time before drugrelease begins.

The number of apertures and the size of each aperture may be selected toprovide a controlled rate of release of the drug. In embodiments inwhich the device is intended to operate primarily or exclusively viadiffusion, the number and size of the apertures may be selected suchthat the total aperture size is large enough to reduce or avoid thedevelopment of osmotic pressure within the reservoir. In embodiments inwhich the housing is permeable to water, the total aperture size mayalso be selected to prevent excessive buildup of hydrostatic pressurewithin the housing, which may increase the volume of fluid in thereservoir causing the housing to swell. For example, an increase inhydrostatic pressure within the reservoir may be prevented by ensuringthe size of the aperture is large enough and/or by spacing a number ofapertures about the housing as appropriate. Within these constraints onaperture size and number, the size and number of apertures for a givendevice or reservoir may be varied in order to achieve a selected rate ofdrug release.

The drug can include essentially any therapeutic, prophylactic, ordiagnostic agent that would be useful to deliver locally into the IPspace. As used herein, the term “drug” with reference to any specificdrug described herein includes its alternative forms, such as saltforms, free acid forms, free base forms, and hydrates. In embodiments,the drug in the drug formulation may be a prodrug. In variousembodiments, the drug formulation may be in a solid form, semi-solidform (e.g., an emulsion, a suspension, a gel or a paste), or liquidform.

In certain embodiments, the drug is water soluble. As used herein, theterm “water soluble” refers to a drug that is more than sparinglysoluble. For example, the water soluble drug may have a solubility equalto or greater than about 10 mg/mL water at 37° C.

In certain embodiments, the drug delivery device is used to treatcancer. In such embodiments, the drug formulation includes a drug thatis used to treat cancerous tumors, such as an antiproliferative agent, acytotoxic agent, a chemotherapeutic agent, or a combination thereof. Inone embodiment, the drug may be selected from cisplatin, carboplatin,oxaliplatin, paclitaxel, and combinations thereof. Otherplatinum-containing anti-cancer drugs, as well as other classes ofanti-cancer drugs, may also be used. The drug formulation may alsoinclude a biologic, such as a monoclonal antibody, a TNF inhibitor, ananti-leukin, or the like. The drug treatment may be coupled with aconventional radiation or surgical therapy targeted to the canceroustissue.

In one embodiment, the reservoir-based device works by allowingperitoneal fluid to enter the device, dissolve the solid or semi-soliddrug, and release the drug in solution. As described below, it has beenfound that the stability of cisplatin is surprisingly preserved withinthe device during in vivo use. Without being bound by a particulartheory, it is believed that the stability is superior over solutions ofcisplatin because the drug is in the solid form within the device. Thisallows for maximum drug efficacy upon release, even months afterimplantation.

In another embodiment, the drug delivery device may be used to treatinfections or for other purposes, such as to manage pain.

In certain embodiments, the drug formulation includes a reduced quantityof excipients, substantially no excipients, or no excipients. In variousembodiments, the drug formulation may include at least one excipient,preferably in a minor amount. Pharmaceutically acceptable excipients areknown in the art and may include lubricants, viscosity modifiers,surface active agents, osmotic agents, diluents, and other non-activeingredients of the formulation intended to facilitate handling,stability, dispersibility, wettability, and/or release kinetics of thedrug. The excipient generally is not of a type or amount that would becharacterized as a matrix material.

In various embodiments, the drug formulation is in a substantially solidform, such as in the form of a drug rod, a drug tablet, a drug pellet, anumber of rods, tablets, or pellets, a compact powder (for example in adisk shape) or a combination thereof, although other configurations arepossible. In a certain embodiments, the drug formulation is in a solidform in order to reduce the overall volume of the drug formulation andthereby reduce the size of the device.

II. Applications and Use

Medicaments for the IP treatment of ovarian cancer are also provided. Incertain embodiments, a medicament includes cisplatin for use in thetreatment of ovarian cancer by intraperitoneal administration into theperitoneal cavity of a patient continuously over a treatment period ofat least 24 hours. For example, the cisplatin may be releasedcontinuously from a drug delivery device implanted in the peritonealcavity of the patient. The drug delivery device may be a device asdescribed above or other drug delivery devices known in the art.

Methods of treating a patient with a drug delivery device are alsoprovided. As used herein, the term “patient” generally refers to a humanpatient, but may include other mammals, such as in medical research,veterinary or livestock applications. The drug delivery device may beimplanted in the patient to release drug locally to essentially anyimplantation site in the patient and may be particularly useful fordelivering drugs that cause undesirable side effects or result ininsufficient bioavailability when delivered systemically. In a preferredembodiment, the implantation site is the peritoneal cavity of a humanpatient in need of treatment for cancer.

In certain embodiments, the method includes implanting a drug deliverydevice within a peritoneal cavity of a patient and thereafter releasingthe drug from the drug delivery device into the peritoneal cavity. Insome embodiments, the method is implemented for treatment of a patienthaving ovarian cancer. The step of implantation of the drug deliverydevice may include a minimally invasive procedure or an open surgicalprocedure. The implantation may be guided using imaging and positioningtechniques and navigation systems known in the art.

In one embodiment in which the drug delivery device is preloaded withdrug and preassembled, the implantation may include loading the drugdelivery device into a delivery instrument and thereafter deploying thedrug delivery device from the delivery instrument into an implantationsite within the peritoneal cavity. The delivery instrument may include alarge bore needle, a cannula, or a catheter, having suitably sizedinternal bore. For example, the device may be inserted through a workingchannel of a laparoscopic instrument inserted into the peritonealcavity. In one embodiment, a sterilized kit is provided that includesthe drug delivery device and one or more delivery instruments.

The drug delivery device may be implanted in association with variousother medical or surgical procedures. For example, the drug deliverydevice may be implanted as part of cytoreduction surgery, such asthrough a laparoscopic port.

Once the device is implanted, the drug formulation is released from thedrug delivery device into the peritoneal cavity. In certain embodiments,the drug is released for an extended treatment period, such as for atleast 24 hours. For example, the drug may be released over a period ofabout one day to about six months, for example from 5 to 60 days, orfrom 10 days to 30 days. In embodiments, the drug is released at arelatively continuous rate over all or at least a majority of thetreatment period.

In embodiments in which the drug delivery device houses a drug in solidor semi-solid form, releasing the drug further includes solubilizing thedrug. For example, the drug may be solubilized with a physiologicalfluid passing into the housing from the implantation environment, such aperitoneal fluid. The physiological fluid may pass through an aperturein the drug delivery device. The fluid may also pass through the housingof the drug delivery device, which may be permeable to fluid.Alternatively, an aqueous fluid may be injected into the reservoir tosolubilize the drug. In other embodiments, the drug is stored in thedevice in semi-solid, gel, slurry, or liquid form, in which case thedrug may or may not need to be solubilized prior to release.

Release of the drug may be driven at least in part by diffusion. In someembodiments, the release may be driven primarily or exclusively bydiffusion. In other embodiments, the release may be driven by diffusionin combination with another release mechanism, in whole or in part. Forexample, in certain embodiments the release rate may be determined atleast in part based on the size of one or more apertures. In some cases,the release rate may be determined primarily or exclusively by the sizeof the aperture or apertures. In still other cases, the release rate maybe further influenced by the location of the aperture, the shape of theapertures, other characteristics of the aperture or device in general,or combinations thereof. In other embodiments, the release of the drugmay be driven by the permeability of the device housing wall.

The device may provide extended, continuous, intermittent, or periodicrelease of a selected quantity of a drug over a period that istherapeutically desirable. In one embodiment, the device can deliver thedesired dose of drug over an extended period, such as 5 days, 7 days, 10days, 14 days, or 20, 25, 30, 45, or 60 days, or more. The rate ofdelivery and dosage of the drug can be selected depending upon the drugbeing delivered and the disease or condition being treated. The releasekinetics of the device can be tailored by varying the number and size ofapertures in the device, varying the composition of the drug formulationtherein, among other device and drug parameters.

In some embodiments, the drug delivery device is resorbable. Inparticular, the housing may be resorbable material, such as a resorbablepolyester and a liquid crystalline polymer. In such embodiments, thedevice may degrade by surface erosion into biocompatible monomers. Thedevice may begin degrading upon implantation and may degrade while thedrug is released. After the drug is released, the device may continuedegrading to the point of loss of mechanical integrity. For example, thedevice may degrade over a suitable period. Thus, the method may furtherinclude permitting any remaining portions of the device, such as thehousing, to degrade in vivo, which may avoid the need for removing orretrieving the device after the drug has been released.

In other embodiments, the drug delivery device is non-resorbable. Insuch embodiments, the device may be removed following implantation. Inone such a case, the method further includes removing the drug deliverydevice following release of the drug. In still other embodiments, thedevice may not be removed even though the device is not resorbable.

III. Methods of Manufacture/Assembly

Methods of making an implantable drug delivery device are also provided.In certain embodiments, the method includes forming a drug formulation,forming a housing, and loading the drug formulation into a reservoir inthe housing through an opening (such as one at the end of the housing),and then closing off the opening.

In certain embodiments, forming a drug formulation entails forming adrug formulation that includes one or more active pharmaceuticalingredients (APIs), and optionally, one or more excipients. The API mayinclude a chemotherapeutic agent, for example, a platinum-containingchemotherapeutic, such as cisplatin. In some embodiments, the drugformulation includes a limited amount of excipient or is substantiallyfree of excipient, so that a relatively higher percentage of the volumeof the drug formulation is API, permitting the delivery of a relativelylarger amount of the API with a relatively smaller volume of drugformulation.

In embodiments, forming the drug formulation may include forming a solidor semi-solid drug formulation. This is particularly desirable because asolid or semi-solid drug formulation may require relatively less spacein the housing, permitting the delivery of a relatively larger amount ofdrug formulation from a reservoir of a given size. Methods of formingsolid or semi-solid drug formulations generally are known in the art,and include granulating the drug formulation to produce a highconcentration drug formulation with specific physicochemical properties(e.g., solubility, dissolution rate). Optionally thereafter, thegranulated or powdered drug formulation may be compacted, for example byusing a tablet press. Desirably, the compacted solid drug formulationhas dimensions and a shape that are substantially similar to that of thereservoir so that it may be easily inserted into and contained in thereservoir.

The reservoir housing may be formed using a variety of methods, such asinjection molding, compression molding, extrusion molding, transfermolding, insert molding, thermoforming, casting, or a combinationthereof. In one embodiment, the housing is formed using precisioninjection molding. The housing is formed with a hollow interior,defining a reservoir for holding the drug formulation.

Forming the device housing also may include forming one or moreapertures through the housing. In particular embodiments, the apertureis formed through the housing and/or through a wall of the tissueinterfacing member, such as by mechanically punching, mechanicaldrilling, or laser drilling one or more holes, or such as by injectionmolding, forming, or casting the housing or tubular body with a holeformed therein. Forming an aperture generally includes sizing andpositioning the aperture to achieve a selected release rate for the drugformulation once the device is implanted. In certain embodiments, thestep of forming the housing may also include forming multiple differentdrug reservoirs in a single housing, such as by forming one or morepartitioning structures in the housing or by inserting one or morepartition structures into the housing once formed.

In one embodiment, loading the housing with the drug formulationincludes placing the drug formulation in the reservoir in the housingand sealing the housing to contain the drug formulation therein. Inembodiments in which the drug formulation is a solid drug formulation,loading the housing may include placing one or more drug rods, pellets,or tablets in the housing. Alternatively, the drug formulation may be ina fluidized form (e.g., melted, in solution with a solvent liquid, or insuspension with a non-solvent liquid) for reservoir loading and thensubsequently solidified (e.g., by cooling or volatilization of theliquid). Loading the housing may include filling the reservoir with thedrug formulation, maximizing the amount of drug that can be deliveredfrom a device of a given size. Sealing the housing may include pluggingthe opening (used for loading-in the drug formulation) with amedical-grade adhesive, a solid plug, or combination thereof.

Device assembly may also include associating one or more releasecontrolling structures with the housing, such as a sheath or coatingplaced over at least a portion of the housing to modulate the passage ofwater into the housing, or a degradable membrane positioned over or inone or more of the apertures to control the initial time of release ofthe drug therethrough.

In certain embodiments, the device is assembled using steriletechniques, for example, assembly in a clean room environment andsterilization using ethylene oxide gas, irradiation, or high intensitypulsed light. The sterilization technique will depend upon thesensitivity of the components used, such as the tendency for polymersand drugs to degrade after exposure to radiation. The device then may bevacuum-sealed in a polymeric package prior to distribution to reduce theamount of moisture or air that could potentially cause any one of thecomponents to become contaminated or prematurely decompose during itsshelf life.

The present disclosure may be further understood with reference to thefollowing non-limiting examples.

IV. Examples

Materials for in vitro release were obtained from VWR International(USA). Cisplatin, A2780 cell line, nickel(II) chloride, sodiumhydroxide, sodium diethyldithiocarbamate trihydrate (DDTC), dimethylsulfoxide and HPLC-grade methanol were obtained from Sigma-Aldrich (St.Louis, Mo., USA). The HPLC column (ODS Hypersil, 250×4.6 mm, 5 μm) waspurchased from Thermo-Scientific (USA). SKOV3-Luc (luciferase-positive)cell line and luciferin were obtained from Caliper LifeSciences(Hopkinton, Mass., USA). Isofluorane was purchased from McKesson (SanFrancisco, Calif., USA). Cell growth media, MTT assay, fetal bovineserum (FBS) were purchased from Invitrogen (NY, USA). BALB/c and nu/numice were purchased from Charles River (MA, USA).

HPLC Sample Preparation

Working solutions of nickel (II) chloride in PBS and DDTC in 0.1M sodiumhydroxide were prepared at 0.1 mg/mL and 0.1 g/mL respectively. Nickelchloride was used as an internal standard while DDTC was used toconjugate cisplatin for UV detection on the HPLC machine. The sampleswere diluted in PBS to a final volume of 500 μL, before adding 50 μL ofeach of nickel chloride and DDTC stock solutions. The sample was thenincubated at 37° C. for 30 minutes before running on HPLC.

HPLC Method

The HPLC method was a modification of the published method by V. Augey,et al. (J. Pharma. and Biomed. Anal. 13, 1173-78). An Agilent 1200 LCsystem was used for cisplatin quantification. The column was heated to30° C. and the sample holder was cooled to 4° C. prior to the run. Amobile phase of 75% methanol in water was used, with a flow rate of 1.4mL/min. The cisplatin peak appeared at 5.1 minutes and the internalstandard peak at 6.0 minutes. A calibration curve was obtained for aconcentration range of 0.1 to 5 μg/mL and was highly linear (r=0.999).

Cisplatin Assay Calibration

Stock cisplatin solution of 1 mg/mL was prepared in saline solution. Thestock solution was then serially diluted to 0.1 μg/mL from 5 μg/mL. 50μL each of the working solutions of DDTC and internal standard was addedto 500 μL of the various concentrations of cisplatin. The calibrationsamples were incubated for 30 min at 37° C. and ran on HPLC with theabove-mentioned parameters. A calibration was run on each day that thesamples were run to ensure accuracy.

Example 1: Fabrication and Assembly of Proof-of-Concept Reservoir Device

Reservoir-based drug delivery devices were injection molded frompoly-L-lactic acid (PPLA). The cylindrical devices were substantiallyshaped as shown in FIG. 3 with an outer diameter of about 3 mm, an innerdiameter of about 2.5 mm, and a height of about 3.5 mm. Each devicehousing 30 was loaded with 10 mg of cisplatin powder. Then, the housingwas sealed by attaching a cap 32, or lid, over the opening of thehousing 32. The lid 32 had a 180 orifice 34 drilled through it. Thehousing components were fabricated by injection molding by MatrixIncorporated (East Providence, R.I., USA). In some devices, additionalholes were drilled (on the cylindrical surface of the device housing)with Cameron CNC Micro Machining Center (Sonora, Calif., USA) to createdevices having various numbers of apertures, for example one device had6 total orifices and one device had 11 total orifices.

Example 2: In Vitro Release of Cisplatin from Reservoir Device

Drug release was accomplished by diffusion through the micromachinedorifice(s) in the device made in Example 1. Fick's First Law ofDiffusion (Equation 1) was used to estimate the rate of drug releasefrom the device.

$\begin{matrix}{\overset{.}{m} = {{- A}*D\; \frac{C_{s}}{\Delta \; x}}} & \left( {{Equation}\mspace{14mu} 1} \right)\end{matrix}$

In Equation 1, {dot over (m)} is the mass diffusion rate (mass per unittime), a is the area of the release orifice (or orifices), D is thediffusion coefficient, C_(s) is the solubility of the drug and Δx is thediffusion distance (assumed to be the depth of the orifice). Thesereservoir-based devices allow for simple control of the release rate byengineering the size and/or number of orifices.

The device was first vacuumed in phosphate-buffered saline (PBS) toreplace air in the device with PBS. This process “activates” the deviceby forming a saturated solution inside the device for release. Thedevice was then released in PBS at 37° C. The release solution waschanged to a fresh PBS solution at various time points to maintain aconstant sink condition around the device. The release solution at eachtime point was then assayed with HPLC to measure the amount of drug thatwas released. This was then plotted with time to obtain the in vitrorelease profile for the device, as shown in FIG. 4. The results showedthat the devices release vary linearly and reproducibly. The 6-orificedevice released cisplatin at a rate of 21 μg/hour in vitro and the11-hole device released at 43 μg/hour.

Example 3: In Vitro Cytotoxicity Study

The in vitro cytotoxicity study involved bathing the SKOV3 cells invarious concentrations of cisplatin over various periods of time inorder to estimate the minimum concentration of cisplatin that the deviceneeds to maintain in the peritoneal cavity to kill tumor cells. Thecisplatin-susceptible cell line A2780 and cisplatin-resistant cell linesSKOV3 and OVCAR3 were used. RPMI 1640 with 20% fetal bovine serum (FBS)was used for culturing A2780 and OVCAR3, and McCoy's 5a cell growthmedia with 10% FBS was used for SKOV3 propagation. The cells were seededin 96-well plates at 10⁴ cells/well. The cells were then incubated incell culture media containing cisplatin concentrations of 0.1 to 10μg/mL over different durations ranging from 2 hours to 7 days. Thecisplatin-containing cell media were refreshed daily to preventdegradation of the drug over time. The control wells contained cellsthat were subjected to cell culture media without cisplatin. Thepercentage cell viability was calculated as a percentage of theuntreated group at each time point.

The results are shown in FIG. 5. 10 μg/mL is used as a positive controlbecause it was shown that 10 μg/mL for 2 hours is the critical conditionto kill ovarian tumor cells. (Royer, et al., Anti-Cancer Drugs 16,1009-16 (2005)). The results show that 0.1 μg/mL is too low to killtumor cells over a period of 7 days. A minimum concentration of about0.5 μg/mL over 7 days should to be maintained to achieve significanttumor cytotoxicity.

Example 4: Pharmacokinetic Study

BALB/c mice were divided into 2 groups: device implantation and IP bolusinjection administration. Five 1-orifice devices were implanted for thisstudy. The animals were sacrificed at various time points in groups of 3after either device implantation or IP bolus injection, to harvest theirperitoneal lavage and blood. Peritoneal lavage was obtained by injecting1 mL of sterile saline into the peritoneum and immediately withdrawingthe solution out. The blood sample was allowed to clot for 30 minutesbefore centrifuging to separate serum from the blood. The lavage andserum samples were assayed for cisplatin concentration and plotted withthe time of treatment. All animal protocols had been approved by theDivision of Comparative Medicine at MIT.

The results of the pharmacokinetics study are shown in FIGS. 6A and B.The results revealed that for IP bolus injection, the serum cisplatinconcentration spiked at about 7 μg/mL and quickly decreased to belowdetection level in about 3 hours. The device group, however, was able toconstantly maintain a very low serum concentration of about 0.1 μg/mL.The device group was also able to maintain a concentration of 0.1 μg/mLin the peritoneal cavity over 7 days while the IP bolus injection groupquickly dropped to zero in about three hours. The concentration ofperitoneal cisplatin concentration that the single-orificereservoir-based device maintained is below the minimum cisplatinconcentration for killing cancer cells. A 6-orifice device (21 μg/hourrelease rate) was, therefore, used for the subsequent experiments.

Example 5: Tumor Induction Study

The tumor induction study was performed in nu/nu mice to validate theanimal model and to elucidate the tumor growth profile. This studyestablished the protocol for the subsequent drug treatment study. 5×10⁵,10⁶, 5×10⁶, 10⁷ SKOV3 luciferase-positive cells suspended in their cellculture media were inoculated in each nu/nu or SCID BEIGE mouse at Day0. The tumors were allowed to grow for up to 35 days and theluminescence intensity was measured twice a week. 10 μg/g of luciferinstock solution (15 mg/mL in sterile DPBS) was injected, and then after10 minutes, the tumors were imaged.

The results are shown in FIG. 7, which shows an initial drop in thebioluminescence value of 5×10⁶ and 10⁷ cells/animal. Presumably this isthe result of only some of the cells remaining viable over time or thesecells being attacked by the mouse's immune system. The tumor cells thatsurvived seeded at various locations in the peritoneal cavity andstabilized by about 7 days. This initial drop in bioluminescenceintensity is not observed for the lower cell number injections,indicating that 5×10⁶ and 10⁷ cells/animal is likely to be excessive.The tumors began to grow exponentially from about Day 21 onwards.

Patients who receive chemotherapeutic treatment in the clinic aretreated after tumor-debulking surgery where the only tumors remainingare small and diffuse. Treatment in this animal model is thereforestarted before the exponential tumor growth, on Day 14, in order tomimic the clinical situation. The animals that were injected with 5×10⁶and 10⁷ cells/animal developed tumors which grew rapidly and formed oneor two tumors larger than 1 cm in diameter in about 50 days. Thisdisease presentation did not mimic the clinical scenario. The tumorsthat remain after surgical tumor resection in patients are distributedthroughout the peritoneal cavity, ideally each with a diameter of lessthan 1 cm.

At Day 14, the tumors for the 10⁷ and 10⁶ cells/mouse were visuallycompared. A reduction of tumor size was observed and the tumors werebetter dispersed in the peritoneal cavity at 10⁶ cells/mouse. A laterexperiment involving treatment of these SCID BEIGE mice revealed thatdue to their severely defective immune system, the mice weresignificantly less tolerant to cisplatin treatment and the study had tobe terminated prematurely. Subsequent experiments proceeded with 10⁶cells/mouse inoculation in nu/nu mice.

Example 6: Treatment Efficacy

The nu/nu mice were inoculated with tumor cells on Day 0 and treatmentwas started on Day 14. 10⁶ SKOV3 cells were inoculated into the mice onDay 0 and treatment (either IP bolus injection at 5 mg/kg orintraperitoneal device implantation) was administered on Day 14. Theanimals were divided into three groups: device group, IP bolus injectionat once per week (lx/wk) and untreated control. The devices weresterilized with ethylene oxide prior to implantation. All animal careguidelines as listed in the animal protocol were followed. The animalswere imaged 2 times a week, similar to the tumor induction study. Theanimals in the toxicity study were sacrificed on day 56 and their organs(kidney, liver, spleen, intestines and bone) were removed immediatelyupon euthanasia to be fixed in 10% formalin overnight. The devices fromthe animals with a device implanted were also retrieved during necropsy.The amount of drug remaining inside the device was measured with HPLC todetermine the quantity of drug that has been released.

Devices with different release rates were tested in the animals. It wasshown the study that the devices that released less than 35 μg/day (arange of 13-32 μg/day) allowed the animals to survive until the end ofthe study. This preliminary data offers significant insight into thephysiologically relevant dose required for tumor burden reductionwithout systemic toxicity. FIG. 8 illustrates the significant tumor massreduction observed in the device and IP treatment groups. The normalizedluminescence in FIG. 9 reflects the relative tumor burden measured inthe device treatment (for release rates <35 ug/day), IP bolus treatment(weekly 5 mg/kg), and no treatment control groups.

Example 7: Toxicity Study

The animals from the treatment efficacy study above were euthanized atthe end of the experiment and their organs were harvested forhistological analysis. Serum samples were also harvested for theanalysis of creatinine levels in the various groups. H&E stain showedthat there was no significant kidney damage in any group of animals.FIG. 10 also shows that there was no significant increase in serumcreatinine levels, indicating no nephrotoxicity in any of the groups.Normal creatinine levels are shown in red.

Bone marrow depletion was the main toxicity observed. Bone marrowdepletion was observed in mice that received more than 35 μg/day fromthe devices and in the IP bolus group, as compared to the controls. Thetoxicity was significantly more pronounced in the IP group with majorloss of myeloid and erythroid cells in the bone marrow. There was nosignificant bone marrow depletion from devices with a dose of less than35 μg/day. The weight loss throughout the duration of the studyillustrated in FIG. 11 also reflects the relative degree of systemictoxicity observed in the three groups. The weekly IP bolus injection isclearly toxic with an observed drop in body weight with every dose. Thebody weight recovers by about 7 days post-dose, however, with repeateddose, significant systemic toxicity is observed.

The SKOV3 tumor resistance cell line was chosen as the animal model.This cell line was obtained from the ascites fluid of a human epithelialovarian cancer patient, and therefore is a good representation ofmetastatic tumors of the ovaries in the peritoneum. The North AmericanFirefly Luciferase gene was a stable transfection from a CMV promoterand had been shown to express the luciferase gene over 13 generations.Only cells of less than 10 generations were used for all the animals sothat the luminescence intensity would be representative of the actualtumor burden. While bioluminescence is not a precise measurement of thetumor load in the animals, it was not feasible to sacrifice asignificant number of animals at every time point to track tumor growth.Moreover, even if the tumor masses were measured at each time point, thesmall tumors embedded in the mesenteric fats could be easily missed out,resulting in inaccuracies. Therefore, bioluminescence tracking is areasonable method to follow tumor growth in this study.

The treatment efficacy study included a group of animals which weretreated with IP bolus injection (10 mg/kg) at a frequency of 1 dose perweek. Tumors in this group remained relatively small. Nephrotoxicitydifferences between the 11-orifice device group and the IP bolusinjection 1 dose per week group show that there is significant tubulardamage in the latter. The pharmacokinetics study suggested that thelower serum cisplatin concentration is most likely the reason for thistoxicity difference. Thus, the 11-orifice device was able to bring aboutmaximum treatment efficacy with minimum renal damage and was proven tobe an ideal treatment modality through both preliminary in vitro and invivo studies. Accordingly, the medicaments, devices, and methodsdescribed herein may decrease morbidity due to catheter relatedcomplications, reduce systemic drug concentration, and improve patients'well-being during the treatment.

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

We claim:
 1. An implantable device for intraperitoneal drug deliverycomprising: an elongated, flexible device which comprises a housingdefining a reservoir that contains a drug in solid or semi-solid form,wherein the device is configured to be wholly deployed within theperitoneal cavity of a patient and continuously release atherapeutically effective amount of the drug over a period of at least24 hours.
 2. The device of claim 1, wherein the housing comprises anelastomeric tube having an outer diameter from about 1 mm to about 5 mm.3. The device of claim 1, wherein the housing has a length from about 25mm to about 100 mm.
 4. The device of claim 1, wherein the device issterilized and further comprises at least one suture loop, at least oneradio-opaque element, or a combination thereof.
 5. The device of claim1, wherein the drug comprises more than 70 percent of a total volume ofthe device.
 6. The device of claim 1, wherein the housing comprises oneor more apertures for releasing the drug in a solubilized form.
 7. Thedevice of claim 1, wherein the drug comprises a chemotherapeutic agent.8. The device of claim 1, wherein the drug comprises cisplatin.
 9. Thedevice of claim 8, which is configured to release the cisplatin in vitroat a rate from about 15 mg/day to about 50 mg/day in phosphate bufferedsaline at 37° C.
 10. The device of claim 8, which is configured torelease the cisplatin in vivo at a rate from about 0.6 mg/hour to about2.5 mg/hour.
 11. The device of claim 8, which is configured to maintaina concentration of the cisplatin in the peritoneal fluid of the patientof at least about 0.5 μg/mL for at least 7 days, while releasing at anaverage rate of no more than 5 mg/day.
 12. The device of claim 11, whichis configured to release cisplatin at an average rate from about 1.5mg/day to about 3.5 mg/day.
 13. The device of claim 8, which containsfrom 500 mg to 1000 mg cisplatin.
 14. The device of claim 8, wherein thehousing comprises a first end, a second end, and an annular wall definedbetween the first and second ends, wherein the reservoir is defined byan inner surface of the annular wall.
 15. The device of claim 14,wherein the annular wall comprises silicone and has one or moreapertures extending therethrough.
 16. An implantable device forintraperitoneal delivery of cisplatin, the device comprising: anelongated housing defining a reservoir that contains cisplatin in asolid or semi-solid form, wherein the device is configured to be whollydeployed within the peritoneal cavity of a patient and continuouslyrelease a therapeutically effective amount of the cisplatin over aperiod of at least 24 hours.
 17. The device of claim 16, which isconfigured to release the cisplatin in vitro at a rate from about 15mg/day to about 50 mg/day in phosphate buffered saline at 37° C.
 18. Animplantable device for intraperitoneal delivery of cisplatin, the devicecomprising: an elongated housing comprises an elastomeric tube having afirst end, a second end, and annular wall between the first and secondends; a reservoir defined at least in part by an inner surface of theannular wall of the elastomeric tube; a drug payload disposed in thereservoir and comprising from 500 to 1000 mg of cisplatin; aradio-opaque element in the housing; and a suture loop provided at oneof the ends, wherein the device is configured to be wholly deployedwithin the peritoneal cavity of a patient and continuously release thecisplatin over a period of at least 24 hours.
 19. The device of claim18, which is configured to release the cisplatin in vitro at a rate fromabout 15 mg/day to about 50 mg/day in phosphate buffered saline at 37°C.
 20. The device of claim 18, which is configured to release thecisplatin in vivo at a rate from about 0.6 mg/hour to about 2.5 mg/hour.